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Cancer

Calcium wave signaling in cancer cells

By | Cancer

Calcium wave signaling in cancer cells

JAI PARKASHa and KAMLESH ASOTRA

Ca2+ functions as an important signaling messenger right from beginning of the life to final moment of the end of the life. Ca2+ is needed at several steps of the cell cycle such as early G1, at the G1/S, and G2/M transitions. The Ca2+ signals in the form of time-dependent changes in intracellular Ca2+ concentrations, [Ca2+]i, are presented as brief spikes organized into regenerative Ca2+ waves. Ca2+-mediated signaling pathways have also been shown to play important roles in carcinogenesis such as transformation of normal cells to cancerous cells, tumor formation and growth, invasion, angiogenesis and metastasis. Since the global Ca2+ oscillations arise from Ca2+ waves initiated locally, it results in stochastic oscillations because although each cell has many IP3Rs and Ca2+ ions, the law of large numbers does not apply to the initiating event which is restricted to very few IP3Rs due to steep Ca2+ concentration gradients. The specific Ca2+ signaling information is likely to be encoded in a calcium code as the amplitude, duration, frequency, waveform or timing of Ca2+ oscillations and decoded again at a later stage. Since Ca2+ channels or pumps involved in regulating Ca2+ signaling pathways show altered expression in cancer, one can target these Ca2+ channels and pumps as therapeutic options to decrease proliferation of cancer cells and to promote their apoptosis. These studies can provide novel insights into alterations in Ca2+ wave patterns in carcinogenesis and lead to development of newer technologies based on Ca2+ waves for the diagnosis and therapy of cancer.

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Tumour suppression by p53: a role for the DNA damage response?

By | Cancer

Tumour suppression by p53: a role for the DNA damage response?

David W. Meek

Loss of p53 function occurs during the development of most, if not all, tumour types. This paves the way for genomic instability, tumour-associated changes in metabolism, insensitivity to apoptotic signals, invasiveness and motility. However, the nature of the causal link between early tumorigenic events and the induction of the p53-mediated checkpoints that constitute a barrier to tumour progression remains uncertain. This Review considers the role of the DNA damage response, which is activated during the early stages of tumour development, in mobilizing the tumour suppression function of p53. The relationship between these events and oncogene-induced p53 activation through the ARF pathway is also discussed.

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Where cancer meets calcium — p53 crosstalk with EF-hands

By | Cancer

Where cancer meets calcium — p53 crosstalk with EF-hands

Mitsuhiko Ikura and Kyoko L. Yap

S100B, an EF-hand Ca2+-binding protein, grasps the C-terminus of the tumor suppressor p53 and inhibits protein kinase C-dependent phosphorylation and acetylation of p53 in a Ca2+-dependent manner. The mode of interaction between S100B and p53 is different from the interactions seen in S100A–annexin complex structures.

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The 1993 Walter Hubert Lecture: The role of the p53 tumour-suppressor gene in tumorigenesis

By | Cancer

The 1993 Walter Hubert Lecture: The role of the p53 tumour-suppressor gene in tumorigenesis

A.J.Levine,M.E.Perry,A.Chang,A.Silver,D.Dittmer,M.Wu & D.Welsh

The p53 tumour-suppress or gene is mutated in 60% of human tumours, and the product of the gene acts as a suppressor of cell division. It is thought that the growth-suppressive effects of p53 are mediated through the transcriptional transactivation activity of the protein. Overexpression of the p53 protein results either in arrest in the GI phase of the cell cycle or in the induction of apoptosis.Both the level of the protein and its transcription all transactivation activity increase following treatment of cells with agents that damage DNA, and it is thought that p53 acts to protect cells against the accumulation of mutations and subsequent conversion to a cancerous state.The induction of p53 level since in cells exposed to gamma-irradiation results in cell cycle arrest in some cells(fibroblasts) and apoptosis in others(thymocytes). Cells lacking p53 have lost this cell cycle control and presumably accumulate damage-induced mutations that result in tumorigenesis. Thus, the role of p53 in suppressing tumorigenesis may be to rescue the cell or organism from the mutagenic effects of DNA damage. Loss of p53 function accelerates the process of tumorigenesis and alters the response of cells to agents that damage DNA, indicating that successful strategies for radiation therapy may well need to take into account the tissue of origin and the status of p53 in the tumour.

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The effect of concurrent radiation and calcium in two cancer cell lines

By | Cancer

The effect of concurrent radiation and calcium in two cancer cell lines

Jessica Billberg

Calcium is an important ubiquitous second messenger regarding the maintenance of cellular homeostasis, and is therefore tightly regulated. Calcium induces cell death when internalised into cancer cells after permeabilization of the cell membrane by electroporation. It is established that radiation causes damage to the lipids and proteins of the cell membrane; and ionizing radiation also causes permeabilization of the cell membrane by peroxidation of the phosphor-lipid layer.

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Examining the relationship between diet-induced acidosis and cancer

By | Cancer

Examining the relationship between diet-induced acidosis and cancer

Ian Forrest Robey

Increased cancer risk is associated with select dietary factors. Dietary lifestyles can alter systemic acid-base balance over time. Acidogenic diets, which are typically high in animal protein and salt and low in fruits and vegetables, can lead to a sub-clinical or low-grade state of metabolic acidosis. The relationship between diet and cancer risk prompts questions about the role of acidosis in the initiation and progression of cancer. Cancer is triggered by genetic and epigenetic perturbations in the normal cell, but it has become clear that microenvironmental and systemic factors exert modifying effects on cancer cell development. While there are no studies showing a direct link between diet-induced acidosis and cancer, acid-base disequilibrium has been shown to modulate molecular activity including adrenal glucocorticoid, insulin growth factor (IGF-1), and adipocyte cytokine signaling, dysregulated cellular metabolism, and osteoclast activation, which may serve as intermediary or downstream effectors of carcinogenesis or tumor promotion. In short, diet-induced acidosis may influence molecular activities at the cellular level that promote carcinogenesis or tumor progression. This review defines the relationship between dietary lifestyle and acid-base balance and discusses the potential consequences of diet-induced acidosis and cancer occurrence or progression.

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Calcium, cancer and killing: The role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells

By | Cancer

Calcium, cancer and killing: The role of calcium in killing cancer cells
by cytotoxic T lymphocytes and natural killer cells

Eva C. Schwarz, Bin Qu, Markus Hoth

Killing cancer cells by cytotoxic T lymphocytes (CTL) and by natural killer (NK) cells is of vital importance. Cancer cell proliferation and apoptosis depend on the intracellular Ca2+ concentration, and the expression of numerous ion channels with the ability to control intracellular Ca2+ concentrations has been correlated with cancer. A rise of intracellular Ca2+ concentrations is also required for efficient CTL and NK cell function and thus for killing their targets, in this case cancer cells. Here, we review the data on Ca2+-dependent killing of cancer cells by CTL and NK cells. In addition, we discuss emerging ideas and present a model how Ca2+ may be used by CTL and NK cells to optimize their cancer cell killing efficiency. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.

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Calcium homeostasis in cancer: A focus on senescence

By | Cancer

Calcium homeostasis in cancer: A focus on senescence

Valerio Farfariello, Oksana Iamshanova, Emmanuelle Germain, Ingrid Fliniaux, Natalia Prevarskaya

Senescence is one of the primary responses to the activation of oncoproteins or down-regulation of tumor suppressors in normal cells and is therefore considered as being anti-tumorigenic but the mechanisms controlling this process are still much unknown. Calcium (Ca2+) plays a major role in many cellular processes and calcium channels control many of the “hallmarks of cancer” but their involvement in tumor initiation is poorly understood and remains unclear.
Therefore, in this article we review some striking senescence-associated characteristics and their potential regulation by Ca2+. The main aim is to produce plausible hypothesis on how calcium homeostasis may participate in cancer-related senescence. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

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Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?

By | Cancer

Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?

Stephen Yiu Chuen Choi, Colin C Collins, Peter W Gout1 and Yuzhuo Wang

The common preference of cancers for lactic acid-generating metabolic energy pathways has led to proposals that their reprogrammed metabolism confers growth advantages such as decreased susceptibility to hypoxic stress. Recent observations, however, suggest that it generates a novel way for cancer survival. There is increasing evidence that cancers can escape immune destruction by suppressing the anti-cancer immune response through maintaining a relatively low pH in their micro-environment. Tumours achieve this by regulating lactic acid secretion via modification of glucose/glutamine metabolisms. We propose that the maintenance by cancers of a relatively low pH in their micro-environment, via regulation of their lactic acid secretion through selective modification of their energy metabolism, is another major mechanism by which cancers can suppress the anti- cancer immune response. Cancer-generated lactic acid could thus be viewed as a critical, immunosuppressive metabolite in the tumour micro-environment rather than a ‘waste product’. This paradigm shift can have major impact on therapeutic strategy development.

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Dairy products, calcium, and prostate cancer risk in the Physicians’ Health Study

By | Cancer

Dairy products, calcium, and prostate cancer risk in the Physicians’ Health Study

June M Chan, Meir J Stampfer, Jing Ma, Peter H Gann, J Michael Gaziano, and Edward L Giovannucci

Background: A high calcium intake, mainly from dairy products, may increase prostate cancer risk by lowering concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a hormone thought to protect against prostate cancer. The results of epidemiologic studies of this hypothesis are inconclusive.

Objective: We investigated the association between dairy product and calcium intakes and prostate cancer risk in the Physicians’ Health Study, a cohort of male US physicians.

Design: At baseline, the men answered abbreviated dietary questionnaires. During 11 y of follow-up, we documented 1012 incident cases of prostate cancer among 20885 men. We estimated dairy calcium intake on the basis of consumption of 5 major dairy products and used logistic regression to estimate relative risk. Results: At baseline, men who consumed >600 mg Ca/d from skim milk had lower plasma 1,25(OH)2D3 concentrations than did those consuming ≤150 mg Ca/d [71 compared with 85 pmol/L (30.06 compared with 35.64 pg/mL); P = 0.005]. Compared with men consuming ≤ 0.5 daily servings of dairy products, those consuming >2.5 servings had a multivariate relative risk of prostate cancer of 1.34 (95% CI: 1.04, 1.71) after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming ≤150 mg Ca/d from dairy products, men consuming >600 mg/d had a 32% higher risk of prostate cancer (95% CI: 1.08, 1.63).

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